Platelets are known for their essential role in maintaining hemostasis but their important contributions to other processes are becoming more apparent. For example, platelets have been shown to have potent bactericidal activity suggesting an important function during infection. Similarly, patients with bloodstream infections typically present with coagulopathies such as disseminated intravascular coagulation. Recently, a new transgenic mouse strain has been developed that can be depleted of platelets for various lengths of time without altering any other blood or immune cell subtype. Preliminary results using this mouse show that they do not mount an effective innate immune response against blood infection with Staphylococcus aureusUSA300 and 100% succumb to the infection within 72 hrs. while >50% of their wild-type counterparts survive the infection for more than 20 days. Platelet-depleted mice are unable to clear the bacteria from blood as effectively as wild-type mice and have increased bacterial burden in kidneys 24 hours after infection. The mechanism(s) behind these observations will be determined through three aims. First, the kinetics of S. aureus clearance from blood will be determined and the important organs and specific cell types responsible for clearance will be identified. Secondly, the ability of platelet to enhance neutrophil-mediated host-defense will be evaluated and the molecules responsible for platelet-enhanced neutrophil activity will be determined. Lastly, the ability of platelets to kill . aureus will be assessed and the molecular mechanism(s) elucidated. The experiments proposed in this grant application will reveal the potential of platelets as major innate immune cells responsible for protection against S. aureus blood infection. It will be important to establih if platelets also combat S. aureus infection via more typical routes of entry (skin abrasions, pneumonia, etc.). This study also gives precedence to the potential of platelets being important innate immune cells protecting from other infectious agents (other bacteria, virus, parasites) as well as their role in protecting against infections.